Treatment of peripheral vascular disease by non-intraarterial administration of prostaglandin E1

ABSTRACT

A method of treating peripheral vascular disease in humans by non-arterial, systemic administration of prostaglandin E 1 , its pharmacologically acceptable salts, lower alkyl esters or amide.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of Ser. No. 716,737, filedAug. 23, 1976, now abandoned.

BACKGROUND OF THE INVENTION

PGE₁ is a naturally occurring prostaglandin. Further, various salts andlower alkyl esters of PGE₁ are known in the art. See, for example, U.S.Pat. No. 3,069,322. Likewise PGE₁ amide is described at Derwent FarmdocCPI 32921W, abstracting French Published Application No. 2,239,458.

PGE₁, its lower alkyl esters, salts, and amide are known to be potentpharmacological agents. In particular, PGE₁ is known to be a potentvasodilator.

However, prostaglandins, including PGE₁, are known to be readily,metabolically inactivated, particularly during pulmonary circulation.Ferreira and Vane (Nature 216, 868, 1967) found that the biologicalactivity of prostaglandin E₁ and E₂, although stable in blood, almostcompletely disappeared in a single pass through the pulmonarycirculation of dogs, cats, and rabbits. Biron (Clin. Res. 16, 112, 1968)confirmed that over 80 percent of prostaglandins perfused through thelung were extracted in rabbits, rats, cats, and dogs. McGiff et al.,(Nature 223, 742, 1969) found that PGE₁ was removed by the lungexceedingly rapidly and concluded that its activities were restrictedessentially to the area between the site of introduction into a vein andthe site of pulmonary circulation where prostaglandins are inactivated.Horton and Jones (Brit. J. Pharmacol. 37, 705, 1969), cited the work ofFerreira and Vane (above) which showed that more than 95 percent of thesmooth muscle stimulating activity of prostaglandin E₂ in the cat andmore than 95 percent of the smooth muscle stimulating activity of PGE₁in the dog were lost on a single passage through the lung, and obtainedlosses of peripheral vasodilator activity of prostaglandin E₁ on passagethrough the lung and liver circulation of the cat and dog which agreedclosely with those noted above. Piper, Vane, and Wyllie (Nature 225,600, 1970) and Piper and Vane (in Prostaglandins, Peptides, and Amines,ed. Mantegazza and Horton, 15, Academic Press, London, 1969) confirmedthese findings and concluded that prostaglandin E₁, E₂, and F₂ α arealmost completely inactivated by the pulmonary circulation of the cat,dog, rat, and guinea pig. They further established that theseprostaglandins were inactivated at all concentrations studied andconcluded that an excess of pulmonary enzyme was available whichmetabolized essentially 100 percent of the PGE reaching the lung.Similarly Samuelsson (Ann. N.Y. Acad. Sci. 180, 138, 1971), injectingtritium labelled PGE into a vein of one arm and removing blood from theother arm found at least 90 percent of the injected prostaglandin hadbeen metabolized during transit through the human lung in 1.5 min. Indouble-labelled studies, they were able to show that the human lungremoved 97 percent of PGE.sub. 2 in 90 seconds and 99.5-100 percent in4.5 min. (Hamberg and Samuelsson, J. Biol. Chem. 246, 6713, 1971). UsingPGF₂ α as a substrate, Granstrom (Eur. J. Biochem. 27, 462, 1971) found97 percent to be removed in 90 seconds and 99.5 percent in 3.5 min.These investigations establish that the prostaglandin E's are convertedto 15-keto metabolites within seconds after reaching the lung and thatthe metabolites are relative inactive.

Thus, heretofore the administration of PGE₁ in the treatment of humanperipheral vascular disease was known only by administration of theprostaglandin into an artery leading to one or more affectedextremities. Accordingly, this intraarterial administration would allowPGE₁ to exert its therapeutic effect at the site of the diseasedvascular beds without first passing through the lung, and thus beforebeing subjected to prostaglandin 15-dehydrogenase, prostaglandin13-reductase or other known prostaglandin-inactivating enzymes of thelung.

However, intraarterial administration as taught in the prior art,represents an especially inconvenient and substantially more traumaticroute of adminstration than other more routinely and conventionallyemployed parenteral routes (e.g., intravenous). Thus, intraarterialadministration requires the continuous supervision by highly skilledmedical professionals.

For a complete discussion of the nature of and clinical manifestationsof human peripheral vascular disease and the method previously known ofits intraarterial treatment with prostaglandins, see South AfricanPatent 74/0149.

Further, the parenteral use of PGE₁ as a pharmacological agent, both fortherapeutic and prophylactic purposes, is known in the art. For example,in addition to South African Patent No. 74/0149, numerous referencesdescribe the use of intravenous and intraarterial prostaglandins,including PGE₁, for maintaining the patency of the ductus arteriosus innewborn infants suffering from the "blue baby" syndrome. See R. B.Elliott, et al., Lancet, Jan. 18, 1975, pp. 140-142; P. M. Olley, etal., Circulation, 53:728 (1976); and F. Coceani, et al., Can. J.Physiol. Pharmacol 51:220 (1973).

SUMMARY OF THE INVENTION

The present invention relates to the surprising and unexpected efficacyof PGE₁ in the treatment of human peripheral vascular disease bynon-arterial, systemic administration.

Accordingly, in a method of treating peripheral vascular diseases in theextremities of humans who have circulatory insufficiencies in saidextremities; which consists essentially of systemic administration tosaid humans of PGE₁ in a pharmaceutical dosage form in an amounteffective to decrease said circulatory insufficiencies, whereby reliefof rest pain or induction of healing of ulcers in said extremitiesoccurs; the present invention provides the improvement which comprises:

administering PGE₁ non-intraarterially.

The terms "peripheral vascular diseases", "circulatory insufficiencies","extremities of humans", "pharmaceutical dosage form", "rest pain", and"healing of ulcers" are used in their ordinarily accepted meanings inthe art, and particularly as described in South African Patent 74/0149.However, the term "pharmaceutical dosage form" of PGE₁ includes theemployment of either PGE₁, any of its known pharmaceutically acceptablesalts, lower alkyl esters, or amide. See, for example, the salts andesters of PGE₁ described in U.S. Pat. No. 3,069,322.

The present invention describes the improvement over the prior artwhereby PGE₁ is administered intravenously, orally, rectally, bucally,sublingually, subcutaneously, vaginally, or by other known, readily andconveniently employed non-arterial systemic routes. For example,intravenous injection is accomplished through any readily accessiblehuman vein ordinarily employed when a substance is to be administered bythe intravenous route. For example, the most convenient, and thus mostpreferred, injection route is through the anticubital vein (the largevein of the arm).

This intravenous route of administration has significant advantages overthe previously known intraarterial method of using PGE₁ in peripheralvascular disease. For example, persons of limited medical training areable to easily and conveniently administer PGE₁ intravenously. Further,the more difficult surgical task of locating the less accessiblearterial blood system and providing the drug thereto is obviated. Alsothe possibility of arterial injury is obviated.

For the oral route of administration, any conventional, stabilized oralformulation is employed, including capsules, compressed tablets, and thelike. When oral formulations require extended stability or will endurevariable or poorly controlled conditions of handling and storage,triacetin solutions of PGE₁ enclosed in gelatin capsules are a preferredoral formulation. See U.S. Pat. No. 3,966,962.

Additionally, the present invention shows surprising and unexpectedefficacy for a route of administration which inherently requires thatthe PGE₁ pass through the lungs before transportation to the diseasedextremity. Additionally, in spite of the passage of the PGE₁ through thelungs before transportation to the extremities, the resultingtherapeutic effect is of a surprising and unexpected duration. Forexample, the diminution or alleviation of rest pain after administrationof PGE₁ often persists for several weeks after termination of treatment.

Further, the present administration of PGE₁ is effective at extremelylow doses. For example, doses of PGE₁ are employed at which no systemichypotensive or vasodilation effects are noted.

Accordingly, the present method proceeds at an intravenous dosage ofabout 1-10 μg./hr., more especially 2-4 μg./hr. and an oral dosage of0.1 to 1.0 mg. every two hours, more especially 0.2 to 0.4 mg. every 2hours.

PGE₁ is most preferably administered once per hour by intravenousinjection or, more preferably infusion over about 10 to 20 min.Alternatively continuous infusion is employed.

Oral dosages are administered 6-7 times per day, during the workinghours. Treatment by other non-intraarterial, systemic routes ofadministration proceeds by a similar dosage schedule, employing dosageswhich maintain equivalent blood levels of PGE₁.

Treatment is continued for one to five days, although three days isordinarily sufficient to assure long lasting therapeutic action. Inparticular, the treatment should continue until subjective (relief ofrest pain) and objective (increase in peripheral skin temperature andhealing of ulcers) improvement in the patient's condition is wellestablished. In the event that systemic or side effects are observed thedosage is lowered below the threshold at which such systemic or sideeffects are observed.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is more particularly understood by the operationand results of the following Examples, describing the best mode for itsexecution. The obvious and equivalent variants of the exemplifiedprocess are, however, likewise further examples of the operation of thepresent invention.

EXAMPLE 1

To the following patients, suffering from peripheral vascular disease,PGE₁ in a saline solution is administered intravenously at a dose of 2-4μg./hr., during a 10 min., period each hour for 3 days. No systemic orside effects are observed. The results on the affected extremities areas follows:

    ______________________________________                                                                    Earlier      Immediate                            Patient       Age    Ulcer- Amputa-                                                                              Rest  Effect on                            No.   Sex     Year   ation  tion   Pain  Rest Pain                            ______________________________________                                        I     Female  81     moderate                                                                             no     moder-                                                                              moderate                                                                ate   improve-                                                                      ment                                 II    Female  68     moderate                                                                             no     severe                                                                              complete                                                                      disappear-                                                                    ance                                 III   Female  85     substan-                                                                             no     slight                                                                              moderate                                                  tial                improve-                                                                      ment                                 IV    Female  65     substan-                                                                             no     severe                                                                              no effect                                                 tial                                                     V     Female  77     slight no     none  --                                   VI    Male    71     slight yes    none  --                                   VII   Female  71     moderate                                                                             yes    severe                                                                              complete                                                                      disappear-                                                                    ance                                 ______________________________________                                    

Following treatment the following longer-term effects are noted:

1. The severe rest pain in patients II and VII disappeared completelyand did not recur for the entire period of observation, now five and oneweeks, respectively.

2. With regard to ulcers, there was a deterioration in patient IV whoseulcers were initially purulent and had steadily increased since theinitiation of treatment. Three other patients, who had not beenconsidered suitable candidates for skin transplantation prior totreatment, underwent transplantation after PGE₁ treatment. Two suchtransplants were successful. Of the remaining three patients, a verydefinite healing has occurred in patients II and VI. The effect cannotyet be evaluated in the third patient.

EXAMPLE 2

Four patients with severe peripheral vascular disease are treated orallywith PGE₁, as follows:

Oral administration of PGE₁ is commenced with two doses of 0.1 mg. perpatient at one hour intervals. Thereafter 0.2 mg. of PGE₁ isadministered every two hours. Dosing is maintained from 8:00 a.m. to8:00 p.m. each day for two or three days, depending upon the improvementnoted for the particular patient. Thereafter treatment is continued anadditional three days at a dose of 0.2 mg. every four hours from 8:00a.m. to 8:00 p.m. during the day.

The efficacy of treatment is determined by the effect on rest pain byinterview, the effect on ulcer healing by visual observation, the effecton macrocirculation to the limbs, as assessed by digital pulseplethysmography and distal blood pressure, and the effect onmicrocirculation as measured by vital capillary microscopy. Assessmentsare performed before the start of treatment and after two of three daysof treatment, the final assessment being made one hour prior to the lastadministration of drug during the day.

The treatment described above yields the following results:

Case 1: The patient is a 73 year old woman with a ten year history ofischemic ulcers of the right foot. The toes of the right foot had beenamputated due to gangrene. For the six months prior to treatment, ulcersare present on the upper portion of the right foot and rest pain in thefoot can be relieved only by placing the foot outside of the bed duringthe night. During treatment with PGE₁ the patient's pain is relievedduring the first day of treatment. The extent of ulceration diminishesafter treatment and signs of healing of the ulcers are apparent with thedrying of the edges of the ulcerated tissue. One week after treatmentbegins, two ulcers of the lateral part of the lower leg are healedcompletely and the coloration of the entire foot is deemed improved. Themacrocirculation and microcirculation are not changed during treatment.Mild diarrhea is observed during the first day of treatment, but noother side effects are noted.

Case 2: The patient is a 70 year old woman with a history ofinsulin-controlled diabetes mellitus for the past twenty-five years.Peripheral vascular disease was diagnosed three years prior to treatmentand in the six months prior to treatment intense nocturnal rest pain hasbeen experienced. Amelioration of rest pain is obtained when patientsits in bed with feet downward. The lateral part of the lower right legexhibits a three to four centimeter ulcer and moderate edema at the timetreatment is initiated. During the treatment with PGE₁ the rest painsubsides such that the regular analgesic therapy is not required. Theulcer begins to dry and heal and eleven days after treatment began therest pains are completely relieved. Macrocirculation is not effected bytreatment. A marked improvement is, however, noted in themicrocirculation in four of five toes of each foot. During the firstday, diarrhea and gastrointestinal pain are reported as side effects,but on successive days of treatment no side effects are observed.

Case 3: The patient is a 78 year old woman with a history of diabetesmellitus for the last nine years. Peripheral vascular disease wasdiagnosed two years prior to the commencement of treatment and eightmonths before treatment rest pain and ulceration of the feet is noted.Prior to the commencement of treatment, intense nocturnal rest pain isevident, requiring the patient to sit up or walk around for relief.Treatment with PGE₁ did not effect rest pain. However, edema decreasedand the ulcers became less purulent. No side effects were noted.Macrocirculation and microcirculation are both unchanged by thetreatment.

Case 4: The patient is a 65 year old man with severe peripheral vasculardisease for the past five years. Three years prior to oral treatmentwith PGE₁, his left leg had been amputated and during the past yearsevere claudication of the right leg and nocturnal rest pain are noted.Four months prior to oral administration of PGE₁, intravenousadministration of PGE₁ had resulted in a three month remission of thesesymptoms. On commencement of oral treatment with PGE₁, the nocturnalrest pain disappears and the claudication is ameliorated such thatwalking tolerance increased from 10 to 150 meters. No side effects areobserved and macrocirculation remains unchanged during treatment.Microcirculation in the fifth toe of the right foot is improved.

I claim:
 1. In the method of treating peripheral vascular disease in theextremities of humans who have circulatory insufficiencies in saidextremities; which consists essentially of systemic administration tosaid humans of PGE₁ in a pharmaceutical dosage form in an amounteffective to decrease said circulatory insufficiencies, whereby reliefof rest pain or induction of healing of ulcers in said extremitiesoccurs; the improvement which comprises:administering PGE₁non-intraarterially in a dosage which does not exceed (a) about 10 μgper hour, when administered intravenously; or (b) the dosage by anyother route which is equivalent to a 10 μg per hour dose intravenously,when administered by said other route.
 2. A method according to claim 1,where the extremities are the lower extremities.
 3. A method accordingto claim 2, wherein the systemic administration is by intravenousinjection.
 4. A method according to claim 3, wherein the systemicadministration is by intravenous infusion.
 5. A method according toclaim 4, wherein said pharmaceutical dosage form of PGE₁ comprises apharmaceutically acceptable salt of PGE.sub..
 6. A method according toclaim 4, wherein said pharmaceutical dosage form of PGE₁ comprises asaline solution of PGE₁.
 7. A method according to claim 4, wherein saidpharmaceutical dosage form of PGE₁ comprises an aqueous solution of alower alkyl ester of PGE₁.
 8. A method according to claim 7, whereinsaid lower alkyl ester of PGE₁ is PGE₁, methyl ester.
 9. A methodaccording to claim 2, wherein the systemic administration is by oraladministration.
 10. A method according to claim 9, wherein saidpharmaceutical dosage form of PGE₁ comprises a pharmaceuticallyacceptable salt of PGE₁.
 11. A method according to claim 9, wherein saidpharmaceutical dosage form of PGE₁ comprises PGE₁, amide.
 12. A methodaccording to claim 9, wherein said pharmaceutical dosage form of PGE₁comprises a lower alkyl ester of PGE₁.
 13. A method according to claim12, wherein said lower alkyl ester of PGE₁ is PGE₁, methyl ester.
 14. Amethod according to claim 9, wherein said pharmaceutical dosage form ofPGE₁ comprises a film-coated tablet containing PGE₁.